Nitrogen heterocycles

ABSTRACT

Hydantoins and N-alkylhydantoins of formula (I) ##STR1## have biological properties related to those of naturally occurring prostaglandins and maybe used in medicine, for example in the treatment of thrombosis.

This invention relates to heterocyclic compounds, their synthesis,compositions containing them, and their use in medicine.

Hydantoin derivatives, defined hereinbelow in formula (I), have beenfound to have pharmacological properties related to those of naturalprostaglandins, as demonstrated by their ability to mimic or antagonisethe physiological effects of the natural prostaglandins in variousbiological preparations. In particular, certain compounds of formula (I)have been found to be potent mimmetics of the anti-platelet aggregatoryproperties of prostaglandin E₁.

In formula (I) ##STR2##

Z is hydrogen or alkyl; one of Z¹ and Z² is represented by the group--CH₂ --X--X¹ --X²

wherein X is phenylene, --C.tbd.C--, cis or trans --CH.tbd.CH-- or --CH₂--CQ₂ -- in which each Q is independently selected from hydrogen andalkyl such as ethyl or the two Q's together form an alkylene radicalhaving four, five or six carbon atoms; X¹ is a covalent bond or astraight or branched alkylene chain having 1 to 6 carbon atomsoptionally having one of its methylene groups replaced by oxa(--O--)provided that at least one carbon atom seperates the oxa group from a--C.tbd.C--, --CH.tbd.CH-- or --CO-- group; and X² is selected from5-tetrazolyl, carboxyl, carboxamide, hydroxymethylene andalkoxycarbonyl;

and the other of Z¹ and Z² is represented by the group --Y--Y¹ --Y² --Y³

wherein Y is --CR₂ --CH₂ -- in which each R is independently selectedfrom hydrogen and methyl; Y¹ is carbonyl, methylene, methylenesubstituted by hydroxyl or methylene substituted by hydroxyl and alkyl;Y² is a covalent bond or straight or branched alkylene having 1 to 7carbon atoms optionally substituted on the carbon adjacent Y¹ by one ortwo groups independently selected from alkyl, bicycloalkyl cycloalkyl;Y³ is hydrogen, hydroxy, alkoxy having 1 to 7, preferably 1 to 4, carbonatoms; cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy or benzyloxy,wherein each of phenyl, benzyl, phenoxy and benzyloxy may be substitutedin the benzene ring by one or more groups selected from hydroxy,halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl and alkylwhich may itself be substituted by one or more halogeno groups; or Y isa bond, --CH₂ --, or --CH₂.CH₂ -- and Y¹, Y² and Y³ taken together forma cycloalkyl group substituted by a hydroxyl group which preferably hasthree carbon atoms separating it from the hydantoin ring.

Unless otherwise stated, in formula (I) and other formulae in thisspecification, alkyl moieties are selected from methyl, ethyl, propyl,butyl, pentyl and hexyl, including all isomers thereof;

For example, in the definitions of Y¹ and Y² the alkyl groups arepreferably methyl; and the alkyl moiety of alkoxycarbonyl is desirablymethyl or ethyl. Similarly alkylene groups have 2 to 4 carbon atoms forexample vinyl.

In formula (I) cycloalkyl groups have 3 to 10 carbon atoms andbicycloalkyl groups have 4 to 10 carbon atoms for example adamantyl.

In a compound of formula (I) the bonding of the divalent phenylene groupmay be ortho, meta or para, and the oxa group is preferably adjacent thephenylene or when X is other than phenylene then X¹ may be --CH₂--O--CH₂ --.

Included in the meaning of compounds of formula (I) are the saltscorresponding to the carboxylic acids and tetrazoles when X² is carboxylor tetrazolyl respectively, and the salts which may also be formed whenZ is hydrogen. Particularly valuable salts for medical purposes arethose having a pharmaceutically acceptable cation such as ammonium orthat of an alkali metal eg. sodium and potassium, an alkaline earthmetal eg. calcium and magnesium, or an organic base, particularly anamine such as ethanolamine. Salts having non-pharmaceutically cationsare included within the ambit of this invention as useful intermediatesto pharmaceutically acceptable salts, or the acids or esters of formula(I).

Except when there is clear indication to the contrary, formula (I) andother formulae in the specification embrace all stereoisomersrepresented therein. In particular such formulae include theenantiomeric forms, such mixtures as are designated racemates, anddiastereoisomers.

It has been found that compounds of formula (I) wherein

Z is hydrogen or alkyl having 1 to 4 carbon atoms, for example methyl orbutyl;

one of Z¹ and Z² is --CH₂ --X--X¹ --X² -- wherein X and X¹ takentogether form alkylene of 3 to 7 in particular 5 carbon atoms, and X² isalkoxycarbonyl, carboxyl or a salt thereof;

and the other of Z¹ and Z² is --Y--Y¹ --Y² --Y³ -- wherein Y, Y¹ and Y²are as hereinbefore defined and Y³ is hydrogen, phenyl or benzyl, or Y²and Y³ together form cycloalkyl of 4 to 7 carbon atoms; haveparticularly interesting prostaglandin-related properties. Within thisdefinition are included the subclass wherein Z is hydrogen and Z¹ is--CH₂ --X--X¹ --X² -- as defined.

The compounds of formula (I) may be synthesised by any method known inthe art for the synthesis of compounds of analogous structure. Forexample, they may be prepared from the corresponding derivatives ofhydantoic acid of formula (II) ##STR3##

wherein G is carboxyl or a derivative thereof such as amide or ester inparticular an alkyl ester, and each of Z, Z¹ and Z² has the same meaningas in formula (I), by cyclisation under acidic conditions or by heatingalone. The reaction may be effected in the absence of a solvent, but ifdesired an inert solvent may be used, for example a hydrocarbon such aspetrol. Alternatively, where G is alkoxycarbonyl, cyclisation may beeffected in the presence of a suitable base, for example an alkoxidesuch as sodium ethoxide.

Compounds of formula (II) are conveniently prepared from an amino acidderivative of formula (III) ##STR4##

wherein G, Z¹ and Z² are as defined in formula (I) provided that G mayalso be nitrile by reaction with cyanic acid or an alkyl iso-cyanatedepending respectively on whether Z is hydrogen or alkyl.

When cyanic acid is used, the cyanic acid is conveniently produced insitu by the use of an alkali metal cyanate, eg. potassium cyanate, andan acid which may be present as an acid addition salt of the compound offormula (III) or a free acid of formula (III) wherein either or both ofR and X² is hydrogen. Alternatively an equivalent amount of mineral acidor an organic acid may be added to the reaction medium. The reaction mayproceed in the absence of a solvent but desirably an inert solvent isused which is preferably polar such as water or a mixture of water withacetone dimethylformamide, dimethylsulphoxide or a lower alkanol such asethanol or it may be a hydrocarbon, an ether or halogenated hydrocarbonsuch as chloroform. Where desired, for example if no solvent is used,the reaction may be promoted by heating the reactants.

Similar reaction conditions may be used when an alkyl isocyanate is usedexcept that it is unnecessary to provide an equivalent amount of acid,as an acid addition salt or otherwise, in the reactants.

Instead of using a cyanate or isocyanate, a compound of formula (III)may be reacted with urea, nitrourea or an N-alkylurea as appropriate. Asolvent is not essential but if desired an inert solvent such as onementioned above may be used, and the reaction is preferably effected atan elevated temperature, for example from 100° to 125° C. buttemperatures upto 150° C. may be employed.

In the above described synthesis, the intermediates of formula (II) neednot be isolated from the reaction mixture and may be converted directlyto compounds of formula (I) under the described reaction conditions.

An intermediate of formula (III) may be conveniently prepared byreaction of a compound of formula (IV) with a compound of formula (V)##STR5##

    Q.sup.2 -Z.sup.2                                           (V)

wherein G, Z¹ and Z² are as defined in formula (III), one of Q¹ and Q²is amino and the other is halogeno, preferably bromo. The reaction maybe carried out by heating in the absence of solvent or in the presenceof an inert solvent such as ethanol.

The intermediates of formula (III) wherein Z² is --Y--Y¹ --Y² --Y³ whenY¹ is carbonyl may also be prepared by reaction of an amine of formula(IV) wherein Q¹ is amino with an unsaturated ketone of formula (VI)

    CR.sub.2 =CH.CO.Y.sup.2.Y.sup.3                            (VI)

wherein Y² and Y³ have the same meaning as in formula (III); thereaction being effected in the presence or absence of an inert solvent,and at room temperature or optionally with heating.

Hydantoins of formula (I) may also be prepared by cyclisation of acompound of formula (VII) ##STR6##

wherein Z, Z¹ and Z² are as defined in formula (I) and G¹ is carboxyl ora reactive derivative thereof such as alkoxycarbonyl eg. ethoxycarbonyl.Compounds of formula (VII) may be cyclised under similar conditions as acompound of formula (II) and conveniently the method used to prepare acompound of formula (VII) is chosen such that the prevailing reactionconditions permit spontaneous cyclisation.

For example, the intermediates of formula (VII) may be prepared byreacting a compound of formula (V) with a compound of formula (VIII)

    Q.sup.2 -Z.sup.2                                           (V) ##STR7##

wherein one of Q¹ and Q² is halogeno, preferably chloro or bromo and theother is amino and each of Z, Z¹, Z² and G¹ have the same meaning as informula (VII). The reaction may be effected by admixture of thereactants or optionally an inert solvent is used and the mixture isheated. Suitable solvents include alkanols, ethers, hydrocarbons andhalogenated hydrocarbons.

The compounds of formula (VIII) may themselves be made by reacting anappropriate carbamic acid derivative, for example an alkyl ester, with acompound of formula (IV), using techniques known to those skilled in theart.

In a method related to those described hereinbefore, the hydantoins offormula (I) may be prepared by reacting a compound of formula (IX)##STR8##

wherein each of Z, Z¹ and Z² has the same meaning as in formula (I) witha carbonic acid derivative. Any carbonic acid derivative known to thoseskilled in the art as appropriate may be used, for example phosgene,diphenylcarbonate or an alkyl haloformate such as ethyl chloroformate.The reaction is desirably effected in the presence of a base, forexample an amine such as triethylamine or di-iso-propyl ethylamine, andusing an inert aprotic solvent such as toluene, dimethylformamide or anether such as diethylether. The reaction may be carried out at roomtemperature but if desired the reaction mixture may be heated.

The intermediates of formula (IX) may be made using methods analogous tothose described above for the preparation of compounds of formula (III).

The hydantoins of formula (I) wherein Z is alkyl may also be prepared byalkylation, using an alkylating agent which may be designated as areactive ester derivative of an alcohol J³ .OH, of a compound of formula(X) ##STR9##

wherein J is hydrogen or alkyl, J¹ is hydrogen or Z¹, J² is hydrogen orZ² and J³ is alkyl, Z¹ or Z², provided that one of J, J¹ and J² ishydrogen and J³ does not have the same value as J, J¹ or J² ; in thedefinition of J¹, J² and J³ each of Z¹ and Z² has the same meaning as informula (I). Suitable reactive ester derivatives include chloride,bromide, iodide and sulphonates such as p-toluenesulphonate,methanesulphonate and benzenesulphonate. The alkylation may be effectedusing reaction conditions which are known in the art to be suitable, forexample in the presence of a base such as an alkalimetal hydride, alkalimetal amide, or alkalimetal alkoxide, typically sodium hydride or asodium alkoxide e.g. sodium methoxide.

The reaction is conveniently carried out in an inert solvent whichsimply acts as a diluent for the reactants such as toluene, dioxan,ether, dimethyl formamide, tetrahydrofuran, dimethylsulphoxide oracetonitrile or when the base is an alkali metal alkoxide then thecorresponding alkanol may be used.

It will be appreciated that the intermediates of formula (X) wherein Jis hydrogen are also compounds of formula (I) and may be prepared by oneof the foregoing methods. The compounds of formula (X) may further beprepared by adaptation of methods already known in the art (see forexample Chemical Reviews (1950) 46, p. 403-425).

A further preparation of compounds of formula (I) is by reduction of acorresponding unsaturated compound of formula (XI) ##STR10##

wherein either Z³ is ═CR--CH₂ --Y¹ --Y² --Y³ and Z⁴ is --CH₂ --X--X¹--X² or Z³ is ═CH--X--X¹ --X² and Z⁴ is --Y--Y¹ --Y² --Y³ in which eachof R, X to X² and Y to Y³ is as defined in formula (I), with a suitablereducing agent.

A suitable reducing agent is stannous chloride which may be used as anaqueous solution optionally in the presence of dilute mineral acid orcatalytic hydrogenation may be effected in the presence of for exampleRaney nickel, platinum, palladium, ruthenium or rhodium. The choice ofreducing agent in a given situation will of course be dictated by thepresence of other reactive groups in the molecule which may themselvesbe susceptible to reduction.

The intermediates of formula (XI) may be prepared by the followingseries of reaction: ##STR11##

In the above formulae Z, Z³, Z⁴ and G have the same meanings as informulae (XI) and (III) respectively, G³ is alkyl for example n-butyland G⁴ is halogeno such as bromo. The formation of (XIII) is analogousto the ring closure involving a compound of formula (II) and compoundsof formula (XIV), are prepared using concentrated mineral acid such ashydrochloric acid.

Tetrazoles of formula (I) may be prepared from corresponding compoundswherein the group --X² is replaced by ##STR12## wherein X³ and X⁴together form a bond (nitrile), X³ is hydrogen or alkyl and X⁴ is alkoxy(imidoester), alkylthio (imidothioester), --NH--NH₂ (amidrazone), oramino (amidine) or R³ is hydroxy and R⁴ is amino (amidoxime). Thereaction is preferably carried out in a polar aprotic liquid medium suchas dimethylformamide using a salt of a hydrazoic acid e.g. sodium azide.However, when X² is replaced by an amidine or amidrazone, a suitablereagent is nitrous acid. If an amidine is reacted with nitrous acid thenreduction of the intermediate nitrosation product, with or without priorisolation, using for example sodium amalgam is required to give thecorresponding tetrazole. The tetrazole precursor may be obtained by wellknown methods, for example the nitrile may be obtained by dehydration ofthe corresponding amide.

The alcohols of formula (I) wherin X² is hydroxymethylene may also beobtained by reduction with an appropriate reducing agent of thecorresponding acid, ester, acid halide, acid anhydride or aldehyde. Theappropriate reducing agent will depend on the particular substrate, butreactants which may be used are sodium in ethanol. In particular acarboxylic acid may for example be converted to a corresponding mixedanhydride with ethylchloroformate in the presence of a base astriethylamine, and subsequently reduced to the alcohol using sodiumborohydride. Similarly an ester may be reduced to the alcohol usingdi-iso-butyl aluminum hydride in an inert solvent such as ether orhydrocarbon such as hexane or benzene. Such alcohols may also beprepared by catalytic hydrogenation.

Alternatively the alcohols of formula (I) wherein X² is hydroxymethylenemay be prepared by hydrolysis of a corresponding halide with anappropriate reagent. For this purpose a hydroxide may be used forexample an aqueous alkali or a suspension of silver oxide in water.

In the synthesis of hydantoins of formula (I) having a hydroxyl group ina side chain it may be desirable to protect this during the course ofthe reaction. This may be readily effected in known manner using aprotecting group such as acyl, aroyl, tetrahydropyran-2-yl,1-ethoxyethyl or aralkyl, for example benzyl.

Removal of protecting groups may be carried out by appropriate methodsknown to those skilled in the art: for example an acyl group may beremoved by acid or base hydrolysis, and a benzyl group by reductivecleavage.

Furthermore a ketone of formula (I) wherein Y¹ is carbonyl may beconverted to the corresponding secondary alcohol by reduction with asuitable reducing agent, such as sodium borohydride. Also, an alcohol offormula (I) wherein Y¹ is --CH.OH-- may be oxidised to the correspondingketone using Jones' reagent, acid dichromate or any other suitablereagent.

Similarly where the compounds of formula (I) have a C.tbd.C or CH═CHbond these may be converted by conventional hydrogenation techniques,for example using a Lindlar type or Adams catalyst, to the correspondingethylenic or saturated compounds as appropriate.

The hydantoins of formula (I) have an asymmetric 5-carbon atom, and afurther asymmetric centre is present in those compounds wherein Y¹includes a hydroxyl group. Such alcohols therefore exist as four isomerswhich are separable by thin layer chromatography or high performanceliquid chromatography into two diastereomers, each of which is a racemicmixture of two isomers. On separation of the diastereomers onediastereomer may be converted to a mixture of the four isomers bytreatment with a base, such as an alkali metal hydroxide, andsubsequently re-separated to provide two diastereomers. Repeated use ofthis technique enables the effectual conversion of one diastereomer tothe other; this may be desirable when one diastereomer has a biologicalactivity preferred to the other.

The corresponding alcohols of formula (III) also exist in four isomericforms. If desired, these may be separated into two epimers andsubsequent cyclisation to a compound of formula (I) retains thestereochemical configuration.

In all of the foregoing chemical procedures it is of course evident thatthe choice of reactant will be dictated in part by the functional groupspresent in the substrate, and where necessary reactants having anappropriate selectivity of action must be used.

The hydantoins of formula (I) are of value in having pharmacologicalproperties related to those of natural prostaglandins; that is, thehydantoins mimic or antagonise the biological effects of members of theprostaglandin (PG) `A`, `B`, `C`, `D`, `E` and `F` series. For example,hydantoins of formula (I) have been found to mimic the antiaggregatoryeffect of PGE₁ on blood platelets, and to antagonise the contractioninduced by PGE₂ or PGF₂ on smooth muscle taken from the rat stomach, ratcolon, chick rectum and guinea pig trachea. In general, antagonisticproperties, as opposed to mimetic, have been observed when using largerdoses of the hydantoins. The pharmacological profile, by which is meantthe relative activities, mimetic or antagonistic, compared with thenatural prostaglandins, will of course vary depending on the specifichydantoin under consideration.

By reason of their prostaglandin-related properties, the hydantoins offormula (I) are useful in the pharmacological characterisation anddifferentiation of the biological activities of the naturalprostaglandins and their `receptors`. The further understanding of thephysiological role of prostaglandins is of course valuable in the searchfor new and improved therapeutic substances.

The hydantoins of formula (I) are also of value as therapeutic agents.In particular hydantoins such as those described previously as having apotent anti-aggregatory effect on blood platelets are useful whenever itis desired to inhibit platelet aggregation or to reduce the adhesivecharacter of platelets, and may be used to treat or prevent theformation of thrombi in mammals, including man. For example, thecompounds are useful in the treatment and prevention of myocardialinfarcts, to treat and prevent thrombosis, to promote patency ofvascular grafts following surgery, and to treat complications ofarteriosclerosis and conditions such as atherosclerosis, blood clottingdefects due to lipermia, and other clinical conditions in which theunderlying aetiology is associated with lipid imbalance orhyperlipidemia. A further use for such compounds is as an additive toblood and other fluids which are used in artificial extra-corporealcirculation and perfusion of isolated body portions.

A group of compounds which have been found particularly valuable asinhibitors of platelet aggregation are those of formula (I) wherein Z ishydrogen; Z¹ is carboxyalkylene wherein the alkylene moiety has 3 to 9carbon atoms; and Z² is a group --(CH₂)₂.CH.OH.Y².Y³ wherein Y² isbranched alkylene having a tertiary carbon atom adjacent thehydroxy-substituted carbon and Y³ is as defined in formula (I), or Y²and Y³ together form cycloalkyl having 3 to 10 carbon atoms. Within thisgroup of compounds, those wherein Z¹ is carboxyhexyl and Y² and Y³together form cycloalkyl having 4 to 7 carbon atoms have been foundespecially active.

It has also been found that hydantoins of formula (I) cause relaxationof vascular smooth muscle in a similar way as do members of theprostaglandin `A` and `E` series. Examples of such compounds are5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin and5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)hydantoin.Compounds relaxing vascular smooth muscle are capable of inducingvasodilation and therefore have antihypertensive properties and areuseful in lowering blood pressure in mammals, including man, and may beused alone or in combination with a β-adrenoceptor blocking agent oranother antihypertensive substance for the treatment of all grades ofhypertension including essential, malignant and secondary hypertension.

The compound 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoinalso mimics the effect of PGE, of antagonising histamine inducedbroncho-constriction. The hydantoins of formula (I) having this propertymay be used in the treatment or prophylaxis of bronchial asthma andbronchitis by alleviating the bronchoconstriction associated with thiscondition.

Hydantoins of formula (I), such as5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)-hydantoin,5-(6-carboxyhexyl)-3-methyl-1-(3-oxo-octyl)hydantoin,5-(6-carboxyhexyl)-1-(3-oxo-octyl)hydantoin and5-(6-carboxyhexyl)-1-(4-phenoxybutyl)hydantoin, which inhibitpentagastrin-induced gastric acid secretion and reduce the formation ofaspirin-induced gastric lesions in rats are useful in reducing excessivegastric secretion, reducing and avoiding gastro-intestinal ulcerformation and accelerating the healing of such ulcers already present inthe gastrointestinal tract whether such ulcers arise spontaneously or asa component of polyglandular adenoma syndromes.

Intravenous infusions of certain hydantoins of formula (I), typically5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, to dogs has been foundto increase urine volume indicating a potential utility for suchcompounds as diuretic agents, the uses of which include the treatment ofoedema for example oedema associated with heart failure, liver failureor kidney failure in man or other mammals.

A further use for hydantoins of formula (I) which mimic the uterinesmooth muscle effects of PGE₂ and PGF₂α is as antifertility agents, inparticular as abortifacients.

The amount of a compound of formula (I) required to achieve the desiredbiological effect will of course depend on a number of factors, forexample, the specific compound chosen, the use for which it is intended,the mode of administration, and the recipient. In general, a daily dosemay be expected to lie in the range of from 1 μg to 20 mg per kilogrambodyweight. For example, an intravenous dose may lie in the range offrom 5 μg to 1 mg/kg which may conveniently be administered as aninfusion of from 0.01 to 50 μg per kilogram per minute. Infusion fluidssuitable for this purpose may contain from 0.001 to 100, for examplefrom 0.01 to 10 μg per millititre. Unit doses may contain from 10 μg to100 mg of a compound of formula (I), for example ampoules for injectionmay contain from 0.01 to 1 mg, and orally administrable unit doseformulations such as tablets or capsules may contain from 0.1 to 50, forexample 2 to 20 mg.

More specifically, when a compound of formula (I) is used to inhibitplatelet aggregation it is generally desirable to achieve aconcentration in the appropriate liquid, whether it be the blood of apatient or a perfusion fluid, of about 1 μg to 10 mg, for example from10 μg to 1 mg, per liter.

The abovementioned doses refer to the acids, amides, esters, alcoholsand tetrazoles of formula (I); where a salt is used, the dose should betaken as referring to the corresponding anion.

For use in the treatment or prophylaxis of the conditions referred toabove, while the hydantoin compounds may be used as the raw chemicalthey are preferably presented with an acceptable carrier therefor as apharmaceutical formulation. The carrier must of course be `acceptable`in the sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. The carriermay be a solid or a liquid, and is preferably formulated with ahydantoin compound as a unit-dose formulation, for example a tablet,which may contain from 0.05% to 95% by weight of the hydantoin compound.Other pharmacologically active substances may also be present informulations of the present invention as indicated above. The hydantoincompounds may be incorporated in the formulations either in the form ofthe acid or the salt or ester thereof, and the formulations may beprepared by any of the well-known techniques of pharmacy consistingessentially of admixture of the components of the formulation.

The formulations include those suitable for oral, rectal, topical(buccal - eg. sub-lingual), the parenteral (that is subcutaneous,intramuscular and intravenous) administration, although the mostsuitable route in any given case will depend on the nature and severityof the condition being treated, and on the nature of the hydantoincompound.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, lozenges or tablets eachcontaining a predetermined amount of hydantoin compound; as a powder orgranules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; as an oil-in-water emulsion; or as a water-in-oilliquid emulsion. Such formulations may be prepared by any of the methodsof pharmacy but all methods include the step of bringing intoassociation the hydantoin compound with the carrier which constitutesone or more accessory ingredients. In general they are prepared byuniformly and intimately admixing the hydantoin compound with liquid orfinely divided solid carriers or both, and then, if necessary, shapingthe product into the desired presentation. For example a tablet may beprepared by compression or moulding a powder or granules of thehydantoin compound, optionally with one or more accessory ingredients.Compressed tablets may be prepared by compressing, in a suitablemachine, the hydantoin compound in a free-flowing form such as a powderor granules optionally mixed with a binder, lubricant, inert diluent,surface active or dispersing agent(s). Moulded tablets may be made bymoulding in a suitable machine the powdered hydantoin compound moistenedwith an inert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising a hydantoin compound in a flavoured basis, usuallysucrose and acacia or tragacanth; and pastilles comprising a hydantoincompound in an inert basis such as gelatin and glycerin; or sucrose andacacia.

Formulations of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous preparations of ahydantoin compound, which preparations are preferably isotonic with theblood of the intended recipient. These preparations are preferablyadministered intravenously, although administration may also be effectedby means of subcutaneous or intramuscular injection. Such preparationsmay be conveniently prepared by admixing the hydantoin compound withwater and rendering the product sterile and isotonic with the blood.

Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories. These may be prepared by admixture of thehydantoin compound with one or more of the conventional solid carriers,for example cocoa butter, and shaping of the resulting mixture.

It will be appreciated from the foregoing that what we will claim maycomprise any novel feature described herein, principally and notexclusively, for example:

(a) The novel compounds of formula (I) as hereinabove defined.

(b) A method for the preparation of the novel compounds of formula (I)as hereinabove described.

(c) A pharmaceutical formulation comprising a compound of formula (I) inassociation with a pharmaceutically acceptable carrier therefor, andmethods for the preparation of such formulations.

(d) A method for lowering blood pressure in a mammal including man whichcomprises administration to the mammal of an effective hypotensive,non-toxic amount of a compound of formula (I).

(e) A method for the treatment or prophylaxis of thrombosis in a mammalor mammalian tissue, including human, which comprises administration ofa non-toxic, effective anti-thrombotic amount of a compound of formula(I).

(f) A method for inducing vasodilation in a mammal, including man,comprising administration to said mammal of a non-toxic effectivevasodilatory amount of a compound of formula (I).

(g) A method for the treatment or prophylaxis of gastric lesions in amammal including man comprising administration to said mammal of anon-toxic effective prophylactic or therapeutic amount of a compound offormula (I).

(h) A method for inducing bronchodilation in a mammal, including man,comprising administration to said mammal of a non-toxic, effectivebronchodilatory amount of a compound of formula (I).

(i) A method for the treatment or prophylaxis of an allergic conditionin a mammal, including man, comprising administration to said mammal ofa non-toxic effective prophylactic or therapeutic amount of a compoundof formula (I).

(j) A method of inducing abortion of a foetus in a mammal includinghuman comprising administration to said mammal of a non-toxic effectiveabortifacient amount of a compound of formula (I).

(k) A method of inducing infertility in a mammal including humancomprising administration to said mammal of a non-toxic effectivecontraceptive amount of a compound of formula (I).

(l) A compound of formula ##STR13## wherein two of J, J¹ and J² are thesame as two of Z, Z¹ and Z² as hereinbefore defined in formula (I)respectively, and the other is hydrogen.

(m) A compound of formula ##STR14## wherein M represents >C═Z³, >CH--CHOor >CH-CH(OG³)₂ and Z, Z³, Z⁴ and G³ are as hereinbefore defined informulae (XI) and (XII) respectively.

(n) A compound of formula ##STR15## wherein M¹ represents -Q¹, asdefined in formula (VIII), or --NH--Z² and Z, Z¹, Z² and G¹ are asdefined in formula (VII) except that G¹ may also be hydrogen.

EXAMPLE 1 Preparation of5-(6-Carboxylhexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)hydantoinA. Diethyl 2-aminononanediote

Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g)were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) andabsolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. Thecooled solution was poured into ice-water, the product was extractedinto ether, and the dried extract was evaporated to give crude diethylacetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil,δ2.2(3H, singlet, --COCH₃), 4.17(6H, multiplet, 3×--OCH₂ --CH₃). Thisamide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2hours, the cooled solution was washed with ether, and the aqueous layerwas decolorised with activated charcoal and evaporated to dryness invacuo. The residual colourless glass was dissolved in the minimumquantity of absolute ethanol and added dropwise to a stirred, cooled(-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride(15.7 g). The resulting solution was set aside at room temperature for 1hour, refluxed for 11/2 hours, cooled, and poured into ice-wateradjusting the pH to 9 with aqueous sodium hydroxide. The mixture wasextracted with ether, and the dried extract was concentrated anddistilled, giving diethyl 2-aminononanedioate (55% yield) as acolourless oil, b.p. 114°-115°/0.02--0.3 mm.

B. Diethyl 2-((4,4-dimethyl-3-oxo-phenylpentyl)amino)nonanediote

To diethyl 2-aminononanedioate (5.18 g) was added dropwise4,4-dimethyl-5-phenylpent-1-en-3-one (3.95 g) with cooling and stirring.The mixture was allowed to stand at room temperature for 21 hours togive diethyl 2-(4,4-dimethyl-3-oxo-5-phenylpentyl)amino)nonanedioate.

C. Diethyl 2-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)amino)nonanedioate

The foregoing crude ketone (5.1 g) was dissolved in absolute ethanol (70ml) and the solution was stirred in an ice-bath during the gradualaddition of sodium borohydride (380 mg). The solution was stirred in theice-bath for a further 10 minutes and then left to stand at roomtemperature for 5 hours. Most of the alcohol was evaporated, water wasadded, and the solution acidified to pH 6. The insoluble oil wasextracted with ether, and the ether solution was dried and evaporated toleave diethyl2-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)amino)nonanedioate as a paleyellow oil which was used without further purification.

D.5-(6-Ethoxycarbonyl-hexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)hydantoinand the corresponding acid

A solution of the above alcohol (8.45 g) in ethanol (37.6 ml) and 2N-hydrochloric acid (18.8 ml) was stirred and cooled in ice during thedropwise addition of a solution of potassium cyanate (3.05 g) in water(5.6 ml). The mixture was allowed to stand at room temperature for 18hours, then the alcohol was evaporated, water was added and theinsoluble oil was extracted with ether. The dried ether solution wasevaporated to leave a viscous oil which was heated on the steam bath for6 hours to give5-(6-ethoxycarbonylhexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)hydantoinas a viscous pale yellow oil.

This ester was added to a mixture of 2 N-sodium hydroxide (25 ml) andwater (60 ml) and the resulting cloudy solution was left at roomtemperature for 2 hours. The solution was washed with ether and theclear alkaline solution was acidified with 2 N-hydrochloric acid and theprecipitated oil was extracted with ether. Evaporation of the driedether solution gave a viscous oil (6.8 g) which was chromatographed on acolumn of silica gel to give5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-5-phenylpentyl)-hydantoinas a colourless viscous oil which solidified, m.p. ca. 115° C.,shrinking from ca. 90° C. being a mixture of diastereomers.Recrystallisation several times from a mixture of ethyl acetate andlight petroleum (b.p. 60°-80° C.) gave one of the diastereomers as smallneedles, m.p. 135°-137° C.

EXAMPLE 2 Preparation of 5-(6-Carboxyhexyl)-1-(3-hydroxyoctyl)hydantoinA. Diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate

Dry ethereal hydrogen bromide, prepared from ether (200 ml) and hydrogenbromide (26.8 g) at 0° C., was added dropwise to a stirred solution ofacrolein (19.15 g) in ether (100 ml) cooled to -25° C. The stirredmixture was kept at this temperature for 1 hour, allowed to come to 0°C., stirred for 1 hour, at 0° C. and then added dropwise to etherealpentyl magnesium bromide (prepared from 1-bromopentane (54 g) magnesium(8.8 g) and ether (120 ml)), maintaining constant reflux. The reactionmixture was decomposed with saturated aqueous ammonium chloride andextracted with ether, and the dried extract was concentrated anddistilled, giving 1-bromo-3-hydroxyoctane as a colourless oil, b.p.68.5°-72.5° C./0.08 mm. A solution of this bromo-alcohol (20.9 g) indihydropyran (17.0 g), was treated with p-toluenesulphonic acid (500 mg)in a little ether, set aside at room temperature for 18 hours, andwashed with aqueous sodium bicarbonate. The organic layer was percolatedthrough silica in 1:9 ether/hexane and the solvent was removed in vacuo,giving 1-bromo-3-(tetrahydropyran-2-yloxy)octane as a colourless oil,δ0.88(3H, triplet, --CH₃) and 4.62(1H, broad, -O-CHR-O-). A solution ofthis tetrahydropyranyl intermediate (15.0 g) and diethyl2-aminononanedioate (13.0 g) in absolute ethanol (100 ml) was refluxedfor 18 hours, the ethanol was removed in vacuo, and the residue wasdiluted with water containing a slight excess of sodium carbonate. Themixture was extracted with dichloromethane, the extract was dried oversodium sulphate and evaporated, and the residue was purified by columnchromatography on silica in 1:4 hexane/ether, giving diethyl2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate as a colourlessviscous oil, δ0.88(3H, triplet --CH₃), 2.28(2H, triplet, -CH₂ -CO₂ Et),2.61(2H, multiplet, -CH₂ -N), 3.20(1H, triplet, N--CHR--CO₂ Et),4.13(4H, multiplet, 2×-O-CH₂ -CH₃), 4.60(1H, broad -O-CHR-O-).

The above aminodiester was alternatively prepared in the followingmanner. Diethyl 2-aminononanedioate (10.40 g) and oct-1-en-3-one (5.04g) were mixed slowly at 0° C. with stirring, and set aside at roomtemperature for 3 hours, giving diethyl 2-(3-oxooctylamino)nonanedioateas a colourless oil, δ2.3(4H, multiplet, -CH₂ -CO₂ Et and NCH₂ CH₂ CO-),3.16(1H, triplet, EtO₂ C-CHR-N), 4.11(2H, quartet, --O--CH₂ --CH₃),4.17(2H, quartet, -O-CH₂ -CH₃). A stirred solution of this ketone (13.5g) in absolute ethanol (140 ml) was treated dropwise at 0° C. withsodium borohydride (665 mg) in absolute ethanol (70 ml), then kept for31/2 hours at room temperature and concentrated at 40° C. in vacuo. Theresidue, dissolved in water, was brought to pH 5 with N-hydrochloricacid and extracted thoroughly with chloroform, the extract was washedwith water, dried, and evaporated, giving diethyl2-(3-hydroxy-octylamino)nonanedioate as a colourless oil. Withoutfurther purification, the latter was dissolved in dihydropyran (14.0ml), treated with ether (10 ml) followed by p-toluenesulphonic acid(6.72 g) in portions, and set aside at room temperature for 18 hours.The reaction solution was diluted with ether, washed with aqueous sodiumcarbonate then water, dried, and evaporated, and the residue waspurified by column chromatography on silica in 1:4 hexane/ether, givingdiethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate identical(n.m.r., i.r. mixed t.l.c.) with that prepared previously.

B. 5-(6-Carboxyhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin

To a solution of diethyl2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate (7.8 g) in ethanol(32 ml) was added a solution of potassium cyanate (3.0 g) in water (6ml). The resulting suspension was stirred and cooled during the gradualaddition of 2 N-hydrochloric acid (16.7 ml). The solution was allowed tostand at room temperature for 22 hours, most of the ethanol wasevaporated, water was added, and the insoluble oil was extracted withether. The ether solution was washed with water, dried over magnesiumsulphate, and evaporated. The yellow oil so obtained (8.0 g) wasdissolved in light petroleum (b.p. 60°-80° C.) and the solution wasrefluxed for 4 hours, evaporated to dryness, and the residual oil washeated on the steambath for 2 hours to give5-(6-ethoxycarbonylhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoinas a yellow oil (7.3 g), which was used without further purification.

A solution of the ester (6.2 g) in 0.5 N-sodium hydroxide solution (80ml) was allowed to stand at room temperature for 21/2 hours after whichthe solution was washed with ether, the aqueous layer was acidified with2 N-hydrochloric acid, and the precipitated oil was extracted withether. The washed and dried ether extract was evaporated to give5-(6-carboxyhexyl)-1-(3-tetrahydropyran-2-yloxy)octyl)hydantoin as ayellow oil.

C. 5-(6-Carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin

This tetrahydropyranyloxy-compound (3.55 g) was dissolved intetrahydrofuran (28 ml) and 5 N-hydrochloric acid (7 ml) and thesolution was left at room temperature for 31/2 hours, and then refluxedfor 30 minutes. Most of the solvent was evaporated, water was added, andthe insoluble oil was extracted with ether. The ether solution waswashed with water, dried over magnesium sulphate and evaporated to give3.15 g. of viscous yellow oil. The oil was purified by chromatography ona column of silica gel, elution first with chloroform and then with amixture of chloroform and methanol (19:1) giving5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin as a very viscous almostcolourless oil, δ0.89 (3H, triplet, --CH₃), 2.34 (2H, triplet, --CH₂--CO₂ H), 2.9-4.2 (4H, complex, --CH₂ --N, CH--N, CH--OH), ca. 5.6 (2H,broad, exchangeable, --CO₂ H, --OH), ca. 9.0 (1H, broad, exchangeable,NH).

Using the method of Example 1 the above identified hydantoin was alsoprepared via the corresponding diethyl2-((3-hydroxyoctyl)amino)nonanedioate.

D. Separation of Diastereomers

The hydantoin resulting from the above described preparations was aviscous oil which by use of HPLC on a column of silica with a mixture ofchloroform, methanol and acetic acid (97:2.5:0.5) as solvent wasseparated into two diastereomers, both of which formed small colourlessneedles of m.p. 76°-78° C. and 63°-65° C. respectively.

The same diastereomers were prepared by cyclisation of the correspondingdiastereomers of formula (III). That is, the mixture of diastereomers ofdiethyl 2-[(3-hydroxyoctyl)amino]nonanedioate; prepared as in Example 1was dissolved in ethanol and an ethereal solution of hydrogen chloridewas added. The solution was evaporated to dryness to leave the mixtureof diastereomeric hydrochlorides as a viscous oil, which partlysolidified on standing. Ether was added and the mass was stirred andcooled to give a crystalline solid, which was collected, washed withether, and dried. The solid was crystallised from ethyl acetate to givesmall colourless plates, m.p. 95°-96.5°, of a pure hydrochloride. Thissalt was suspended in dilute sodium hydroxide solution and shaken withether, and the separated ether solution was washed, dried and evaporatedto give one of the diastereomers (A) of diethyl2-[(3-hydroxyoctyl)amino]nonanedioate as a colourless oil.

The ether filtrate remaining after collection of the original solidhydrochloride was evaporated to leave an oily hydrochloride, which wasconverted to base as described above to give the almost pure seconddiastereomer (B) of diethyl 2-[3-hydroxyoctyl)amino]nonanedioate as acolourless oil.

By the method described in Example 1, the above diastereomer (A) wasconverted into a single diastereomer of5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, which crystallised froma mixture of ethyl acetate and light petroleum (b.p. 60°-80°) as smallcolourless needles; m.p. 63°-65°.

Similarly the above diastereomer (B) was converted into the seconddiastereomer of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, whichcrystallised from ethyl acetate-light petroleum (b.p. 60°-80°) as smallcolourless needles, m.p. 76°-78°.

E. Interconversion of the diastereomers

A solution of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin(diastereomer of m.p. 76°-78°) (100 mg) in N-sodium hydroxide solution(3 ml) was allowed to stand at room temperature for 19 hours. Thesolution was acidified and extracted with ether, and the ether extractwas washed with water, dried and evaporated to leave a viscous oil. Bymeans of high performance liquid chromatography this oil was separatedinto the two diastereomers of5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin, m.p. 76°-78° C.identical with the starting material (ca. 40 mg) and m.p. 63°-65° C.(ca. 40 mg) identical with the diastereomer (A) described above.

In similar fashion, the diastereomer of m.p. 63°-65° C. was convertedinto a mixture of approximately equal quantitites of itself with thediastereomer of m.p. 76°-78° C., and the pure diastereomers wereisolated by means of high performance liquid chromatography.

EXAMPLES 3 TO 27

By a series of reactions analogous to that described in Example 1, usingthe appropriate vinyl ketones as starting materials, were prepared:

(3a) diethyl 2-((3-oxopentyl)amino)nonanedioate;

(4a) diethyl 2-((3-oxo-4,4-dimethylpentyl)amino)nonanedioate;

(5a) diethyl-2-((3-oxo-4-methylpentyl)amino)nonanedioate;

(6a) diethyl 2-((3-oxononyl)amino)nonanedioate;

(7a) diethyl 2-((3-oxo-4-methyloctyl)amino)nonanedioate;

(8a) diethyl 2-((3-oxodecyl)amino)nonanedioate;

(9a) diethyl 2-((3-oxo-4,4-dimethyloctyl)amino)nonanedioate;

(10a) diethyl 2-((3-oxo-4-ethylhexyl)amino)nonanedioate;

(11a) diethyl 2-((3-cyclobutyl-3-oxopropyl)amino)nonanedioate;

(12a) diethyl 2-((3-cyclopentyl-3-oxopropyl)amino)nonanedioate;

(13a) diethyl2-((3-oxo-4,4-dimethyl-5-(3-trifluoromethylphenyl)pentyl)amino)nonanedioate;

(14a) diethyl 2-((3-cyclohexyl-3-oxopropyl)amino)nonanediaote;

(15a) diethyl 2-((3-cycloheptyl)-3-oxopropyl)amino)nonanedioate;

(16a) diethyl 2-((3-oxo-4-phenylpropyl)amino)nonanedioate;

(17a) diethyl 2-((3-oxo-4-phenylbutyl)amino)nonanedioate;

(18a) diethyl 2-((3-oxooctyl)amino)pentanedioate;

(19a) diethyl 2-((3-oxooctyl)amino)undecanedioate;

(20a) ethyl2-((3-oxooctyl)amino)-3-(3-ethoxycarbonylmethoxyphenyl)propionate;

(21a) ethyl2-((3-oxo-4,4-dimethylpentyl)amino)-3-(3-ethoxycarbonylmethoxyphenyl)propionate;

(22a) ethyl2-(3-oxooctylamino)-3-(3-(2-ethoxycarbonylethyl)phenyl)propionate;

(23a) ethyl2-(3-cyclobutyl-3-oxopropylamino)-3-(3-(2-ethoxycarbonylethylphenyl)propionate;

(24a) ethyl2-(3-cyclopentyl-3-oxopropylamino)-3-(3-(2-ethoxycarbonylethylphenyl)propionate;

(25a) ethyl2-(3-cyclohexyl-3-oxopropylamino)-3-(3-(2-ethoxycarbonylethylphenyl)propionate;

(26a) diethyl 2-(3-oxooctylamino)-7-oxanonanedioate; and

(27a) diethyl 2-(3-cyclopentyl-3-oxopropylamino)-7-oxanonanedioate;which were converted to the corresponding hydroxy compounds:

(3b) diethyl 2-((3-hydroxypentyl)amino)nonanedioate;

(4b) diethyl 2-((3-hydroxy-4,4-dimethylpentyl)amino)nonanedioate;

(5b) diethyl 2-((3-hydroxy-4-methylpentyl)amino)nonanedioate;

(6b) diethyl 2-((3-hydroxynonyl)amino)nonanedioate;

(7b) diethyl 2-((3-hydroxy-4-methyloctyl)amino)nonanedioate;

(8b) diethyl 2-((3-hydroxydecyl)amino)nonanedioate;

(9b) diethyl 2-((3-hydroxy-4,4-dimethyloctyl)amino)nonanedioate;

(10b) diethyl 2-((3-hydroxy-4-ethylhexyl)amino)nonanedioate;

(11b) diethyl 2-((3-cyclobutyl-3-hydroxypropyl)amino)nonanedioate;

(12b) diethyl 2-((3-cyclopentyl-3-hydroxypropyl)amino)nonanedioate;

(13b) diethyl2-((3-hydroxy-4,4-dimethyl-5-(3-trifluoromethylphenyl)pentyl)amino)nonanedioate;

(14b) diethyl 2-((3-cyclohexyl-3-hydroxypropyl)amino)nonanedioate;

(15b) diethyl 2-((3-cycloheptyl-3-hydroxypropyl)amino)nonanedioate;

(16b) diethyl 2-((3-hydroxy-3-phenylpropyl)amino)nonanedioate;

(17b) diethyl 2-((3-hydroxy-4-phenylbutyl)amino)nonanedioate;

(18b) diethyl 2-((3-hydroxyoctyl)amino)pentanedioate;

(19b) diethyl 2-((3-hydroxyoctyl)amino)undecanedioate;

(20b) ethyl2-((3-hydroxyoctyl)amino)-3-(3-ethoxycarbonylmethoxyphenyl)propionate;

(21b) ethyl2-((3-hydroxy-4,4-dimethylpentyl)amino)-3-(3-ethoxycarbonylmethoxyphenyl)propionate;

(22b) ethyl2-((3-hydroxyoctylamino)-3-(3-(2-ethoxycarboylethylphenyl)propionate;

(23b) ethyl2-((3-cyclobutyl-3-hydroxypropylamino)-3-(3-(2-ethoxycarbonylethylphenyl)-propionate;

(24b) ethyl2-((3-cyclopentyl-3-hydroxypropylamino-3-(3-(2-ethoxycarbonylethylphenyl)propionate;

(25b) ethyl2-(3-cyclohexyl-3-hydroxypropylamino)-3-(3-(2-ethoxycarbonylethylphenyl)propionate;

(26b) diethyl 2-(3-hydroxyoctylamino)-7-oxanonanedioate; and

(27b) diethyl 2-(3-cyclopentyl-3-hydroxypropylamino)-7-oxa-nonanedioatefrom which are prepared the following hydantoins of formula (I) whichwhere indicated were separated by HPLC to provide two diastereomershaving the stated melting points.

(3c) 5-(6-carboxyhexyl)-1-(3-hydroxypentyl)hydantoin, a colourless oil,diastereomers 71°-73° and 56°-58°;

(4c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin,diastereomers 114°-115° and 144°-146°;

(5c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4-methylpentyl)hydantoin, m.p. ca.70°-80°, diastereomers 73°-76° and 110 -111°;

(6c) 5-(6-carboxyhexyl)-1-(3-hydroxynonyl)hydantoin, a viscous oil;

(7c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4-methyloctyl)hydantoin, a viscousoil;

(8c) 5-(6-carboxyhexyl)-1-(3-hydroxydecyl)hydantoin, a viscous oil,diastereomers 68°-70° and 82°-83°;

(9c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin ascolourless crystals, m.p. 90°-98°, one diastere omer isolated bycrystallisation from ethyl acetate m.p. 103°-104°;

(10c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4-ethylhexyl)hydantoin, m.p.70°-80°, diastereomers 82°-84° and 120°-122°;

(11c) 5-(6-carboxyhexyl)-1-(3-cyclobutyl-3-hydroxypropyl)hydantoin,diastereomers 114°-116° and 103°-105°;

(12c) 5-(6-carboxyhexyl)-1-(3-cyclopentyl-3-hydroxypropyl)hydantoin,diastereomers 116°-117° and 97°-99°;

(13c)5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyl-5-m-trifluoromethylphenylpentyl)hydantoin,diastereomers 118°-120° and 145°-147°;

(14c) 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin,diastereomers 96°-98° and 124°-126°;

(15c) 5-(6-carboxyhexyl)-1-(3-cycloheptyl-3-hydroxypropyl)hydantoin,m.p. ca. 70°-76°, diastereomers 107°-109° and 107°-109°;

(16c) 5-(6-carboxyhexyl)-1-(3-hydroxy-3-phenylpropyl)hydantoin,diastereomers both forming colourless viscous oils;

(17c) 5-(6-carboxyhexyl)-1-(3-hydroxy-4-phenylbutyl)hydantoin,diastereomers 102°-104° and 61°-63°;

(18c) 5-(3-carboxypropyl)-1-(3-hydroxyoctyl)hydantoin, diastereomersboth forming colourless viscous oils;

(19c) 5-(8-carboxyoctyl)-1-(3-hydroxyoctyl)hydantoin, diastereomers57°-60° and 69°-71°;

(20c) 5-(3-carboxymethoxybenzyl)-1-(3-hydroxyoctyl)hydantoin, acolourless meringue;

(21c)5-(3-carboxymethoxybenzyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin;diastereomers of the corresponding ethyl ester m.p. 100°-103° and151°-154°;

(22c) 5-(3-(2-carboxyethylbenzyl))-1-(3-hydroxyoctyl)hydantoin; onediastereomer m.p. 82°-86°;

(23c)5-(3-(2-carboxyethylbenzyl))-1-(3-cyclobutyl-3-hydroxypropyl)hydantoin;one diastereomer 118°-121°;

(24c)5-(3-(2-carboxyethylbenzyl))-1-(3-cyclopentyl-3-hydroxypropyl)hydantoin;one diastereomer 140°-143°;

(25c)5-(3-(2-carboxyethylbenzyl))-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin;

(26c) 5-(4-carboxymethoxybutyl)-1-(3-hydroxyoctyl)hydantoin; and

(27c)5-(4-carboxymethoxybutyl)-1-(3-cyclopentyl-1-hydroxypropyl)hydantoin;all of which were obtained via the corresponding ethyl ester.

Starting materials used in the above procedures were prepared asfollows:

A. EXAMPLES 18 AND 19

Using the procedure described in Example 1A were prepared diethyl2-aminopentanedioate, b.p. 93°-96°/0.02 mm n_(D) ²⁴ 1.4425 and diethyl2-aminoandecanedioate b.p. 160°/0.1 mm which were used in Examples 18and 19 respectively.

B. Ethyl 2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate

Diethyl acetamidomalonate (2.60 g) and ethyl3-(chloromethyl)phenoxyacetate (Robertson, J. Chem. Soc. (1933), 492;U.S. Pat. No. 3,933,895) (2.39 g) were dissolved in ethanolic ethoxide(prepared from sodium (230 mg) and absolute ethanol (10 ml)) and themixture refluxed for 19 hours. The cooled solution was poured intoice-water, the product was extracted into ether, and the dried extractevaporated. The residual gum was crystallised from ether/hexane to givediethyl acetamido-(3-ethoxycarbonylmethoxyphenyl)malonate as whiteprisms, m.p. 98.5°-101.5°. This derivative (1.90 g) was refluxed with10% aqueous hydrochloric acid (25 ml) for 31/2 hours and the cooledsolution was evaporated to dryness in vacuo. The residual white solidwas dissolved in the minimum quantity of absolute ethanol and addeddropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (15ml) and thionyl chloride (1.64 g). The resulting solution was set asideat room temperature for 18 hours, refluxed for 1 hour, cooled, andpoured into ice-water, adjusting the pH to 9-10 with aqueous sodiumhydroxide. The mixture was extracted with ether, and the dried extractwas concentrated, giving ethyl2-amino-3-(3-ethoxycarbonylmethoxyphenyl)propionate as a colourless oil,which was used without further purification in Examples 20 and 21.

C. Ethyl 2-amino-3-(3-(2-ethoxycarbonylethyl)phenyl)propionate

A solution of di-isopropylamine (4.04 g) and butyl-lithium (25 ml, 1.60M in hexane) in dry tetrahydrofuran (40.0 ml), stirred at -78° under drynitrogen, was treated over 5 minutes with t-butyl acetate (4.64 g). Tothis solution was added, over 5 minutes, a solution ofα,α'-dibromo-m-xylene (11.60 g) and dry hexamethylphosphoramide (1.42 g)in dry tetrahydrofuran (8.0 ml). The resulting yellow solution wasstirred at -78° for 1/2 hour, then allowed to warm to room temperatureover 3 hours. Excess ice-water was added, and the mixture extracted withether, and the extract washed with 1 N hydrochloric acid (60 ml) thenwater. The dried extract was concentrated in vacuo, to give a yellow oilwhich was purified by column chromatography on silica, eluting with 1:1ether:hexane, giving t-butyl 3-(3-bromomethylphenyl)propionate as acolourless oil. Using the method described in the last foregoingparagraph this was converted to the desired diethylester which was usedin each of Examples 22 to 25.

D. Diethyl 2-amino-7-oxa-nonanedioate

This was prepared from ethyl 4-bromobutoxyacetate (Merck, Ger. Offen.2,354,085) by a series of reactions analogous to that described inparagraph B above and was obtained as a colourless oil, b.p.120°-121°/0.005 mm. It was used in Examples 26 and 27.

EXAMPLE 28 Preparation of 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin

Diethyl 2-(3-oxooctylamino)nonanedioate (7.7 g) prepared by the methoddescribed in Example 1B was treated with potassium cyanate andhydrochloric acid to give5-(6-ethoxycarbonylhexyl)-1-(3-oxo-octyl)hydantoin. Hydrolysis of thisester using sodium hydroxide solution gave5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin as a viscous oil, whichcrystallised to a low-melting solid.

EXAMPLE 29 Preparation of 5-(6-carboxyhexyl)-1-(5-phenylpentyl)hydantoin

A mixture of diethyl 2-aminononanedioate (25.9 g) and 5-phenylpentylbromide (22.7 g) was heated in a bath at 100° C. for 3 hours. Aftercooling, ether (100 ml) was added to the mixture, which was then allowedto stand for 2 hours, at 0° C. The colourless solid (21.95 g) whichcrystallised was collected and dried. This diethyl(2-((5-phenylpentyl)amino)nonanedioate hydrobromide melted at 70°-72° C.

A solution of this hydrobromide (4.86 g) in ethanol (20 ml) and 2N-hydrochloric acid (5 ml) was cooled in ice and stirred during thegradual addition of a solution of potassium cyanate (1.62 g) in water (5ml), after which the solution was allowed to stand at room temperaturefor 18 hours. The alcohol was evaporated, water was added, the insolubleoil was extracted with ether, and the ethereal extract was dried andevaporated to leave a pale yellow oil. This material was heated on thesteam bath for 6 hours to give5-(6-ethoxycarbonylhexyl)-1-(5-phenylpentyl)hydantoin.

The foregoing ester (4.0 g) was hydrolysed by treatment with dilutesodium hydroxide solution and the product was purified by chromatographyon silica gel, to give 5-(6-carboxyhexyl)-1-(5-phenylpentyl)hydantoincrystallising from ethyl acetate-light petroleum (b.p. 60°-80° C.) incolourless prismatic needles, m.p. 90°-92° C.

EXAMPLES 29 TO 35

By a series of reactions analogous to that described in Example 28 usingthe appropriate alkyl halides were prepared:

(29a) diethyl 2-octylaminononanedioate;

(30a) diethyl 2-(4-propoxybutyl)aminononanedioate;

(31a) diethyl 2-(4-phenoxybutyl)aminononanedioate;

(32a) diethyl 2-(4-m-trifluoromethylphenoxybutyl)aminononanedioate;

(33a) diethyl 2-(3-m-tolyloxypropyl)aminononanedioate;

(34a) diethyl 2-(3-hydroxypropyl)aminononanedioate; and

(35a) diethyl 2-(3-hydroxy-3-methyloctyl)aminononanedioate which wereconverted to the desired hydantoins:

(29b) 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin, m.p. 46°-48°;

(29c) 5-(6-carboxyhexyl)-1-octylhydantoin, m.p. 88°-89°;

(30b) 5-(6-carboxyhexyl)-1-(4-propoxybutyl)hydantoin, m.p. 72°-74°;

(31b) 5-(6-carboxyhexyl)-1-(4-phenoxybutyl)hydantoin, m.p. 88°-90°;

(32b) 5-(6-carboxyhexyl)-1-(4-m-trifluoromethylphenoxybutyl)hydantoin,m.p. 51°-54°;

(33b) 5-(6-carboxyhexyl)-1-(3-m-tolyloxypropyl)hydantoin, a colourlessviscous oil;

(34b) 5-(6-carboxyhexyl)-1-(3-hydroxypropyl)hydantoin, m.p. 111°-113°;and

(35b) 5-(6-carboxyhexyl)-1-(3-hydroxy-3-methyloctyl)hydantoin, a viscousoil.

EXAMPLE 36 Preparation of 1-(6-Carboxyhexyl)-5-octyl hydantoin

2-Aminodecanoic acid (J. Am. Chem. Soc., 1946, 68, 450) (16.0 g) wasadded in portions to a cooled (-10° C.) mixture of absolute ethanol (70ml) and thionyl chloride (6 ml) with stirring. The resulting solutionwas set aside for 2 hours, at room temperature, refluxed for 1 hour,cooled, poured into ice-water, and the pH of the solution was adjustedto 9 with aqueous sodium hydroxide. The mixture was extracted withether, the extract was dried, concentrated, then distilled, giving ethyl2-aminodecanoate (75%) as a colourless oil, b.p. 82°-84° C./0.2 mm.

A solution of the above aminoester (18 g) and ethyl 7-bromoheptanoate(20 g) in absolute ethanol (50 ml) was refluxed for 24 hours, and theethanol was then evaporated. Addition of ether precipitated ahydrobromide salt, m.p. 98° C., which was dissolved in a littledichloromethane, treated with an equivalent of triethylamine, washedthoroughly with water, and dried; removal of the solvent gave ethyl2-(6-ethoxycarbonylhexylamino)decanoate (52%) as a colourless viscousoil, b.p. 142°-144° C./0.001 mm.

Ethyl 2-(6-ethoxycarbonylhexylamino)decanoate (7.4 g) was reacted withpotassium cyanate and hydrochloric acid to give1-(6-ethoxycarbonylhexyl)-5-octylhydantoin which formed colourlesscrystals, m.p. 68°-70° C., from light petroleum (b.p. 60°-80° C.).

This ester (4.0 g) was hydrolysed with sodium hydroxide solution to give1-(6-carboxyhexyl)-5-octylhydantoin which crystallised from a mixture ofethyl acetate and light petroleum (b.p. 60°-80° C.) as colourlessneedles, m.p. 65°-66° C.

EXAMPLE 37 Preparation of 5-(6-carboxyhexyl)-3-methyl-1-octylhydantoin

A solution of diethyl 2-octylaminononanedioate (742 mg) and methylisocyanate (120 mg) in dry ether (7.5 ml) was allowed to stand at roomtemperature for 48 hours, after which time the ether was evaporated toleave a pale yellow oil (800 mg). The oil was heated on the steam bathfor 2 hours to give 5-(6-ethoxycarbonyl)-3-methyl-1-octylhydantoin as ayellow oil.

The ester (650 mg) was hydrolysed by standing in solution in ethanol(2.4 ml) and 5 N-sodium hydroxide solution (0.6 ml) for 3 hours at roomtemperature. After evaporation of the ethanol, the acidic product wasisolated by extraction with ether, and purified by chromatography on acolumn of silica gel to give5-(6-carboxyhexyl)-3-methyl-1-octylhydantoin as a colourless oil.

EXAMPLE 38 Preparation of5-(6-carboxyhexyl)-3-methyl-1-(3-hydroxyoctyl)hydantoin

Diethyl 2-((3-oxooctyl)amino)nonanedioate (Example 28) was allowed toreact with methyl isocyanate as described in Example 37 to give5-(6-ethoxycarbonylhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, which washydrolysed to 5-(6-carboxyhexyl)-3-methyl-1-(3-oxooctyl) hydantoin acolourless oil.

This keto-acid (1.23 g) was dissolved in 0.25 N-sodium hydroxidesolution (15 ml) and the solution was stirred in an ice-bath during theaddition of sodium borohydride (63 mg). After 3 hours' stirring at roomtemperature, the solution was acidified and extracted with ether. Thewashed and dried ether extract was evaporated to leave an oil which waspurified by chromatography on a column of silica using a mixture ofchloroform and methanol (50:1) as eluant to give5-(6-carboxyhexyl)-3-methyl-1-(3-hydroxyoctyl)hydantoin as a colourlessviscous oil.

EXAMPLE 39 Preparation of 1-(6-Carboxyhexyl)-3-methyl-5-octylhydantoin

By the method described in Example 37, ethyl2-(6-ethoxycarbonylhexylamino)decanoate (Example 36) was converted into1-(6-ethoxycarbonylhexyl)-3-methyl-5-octylhydantoin, and thence byhydrolysis into 1-(6-carboxyhexyl)-3-methyl-5-octylhydantoin, isolatedas a colourless oil.

EXAMPLE 40 Preparation of 3-Butyl-5-(6-carboxyhexyl)-1-octylhydantoin

To a solution of sodium (308 mg) in ethanol (40 ml) was added5-(6-ethoxycarbonylhexyl)-1-octylhydantoin (see Example 29b), followedby butyl bromide (1.8 g), and the solution was refluxed for 24 hours.The solvent was evaporated, water was added and the insoluble oil wasextracted with ether. The washed and dried extract was evaporated togive 3-butyl-5-(6-ethoxycarbonylhexyl)-1-octylhydantoin.

This ester (3.2 g) was dissolved in ethanol (15 ml) and 2 N-sodiumhydroxide (15 ml) and left at room temperature for 1 hour. The acidicproduct was isolated by extraction with ether and purified bychromatography on silica gel to give 3-butyl-5-(6-carboxyhexyl)-1-octylhydantoin as a colourless oil.

EXAMPLE 41 Preparation of 3-Butyl-1-(6-carboxyhexyl)-5-octylhydantoin

By the method of Example 40, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin(see Example 36) was converted into3-butyl-1-(6-ethoxycarbonylhexyl)-5-octylhydantoin, which was hydrolysedto give 3-butyl-1-(6-carboxyhexyl)-5-octylhydantoin as a colourless oil.

EXAMPLE 42 Preparation of5-(6-Carboxyhex-2-ynyl)-1-(3-hydroxyoctyl)hydantoin

Under the reaction conditions described in Example 1A diethylacetamidomalonate and methyl 7-bromohept-5-ynoate reacted to givediethyl acetamido-(6-methoxycarbonylhex-2-ynyl)malonate as a yellow oil.

This crude product was hydrolysed by boiling with 5N-hydrochloric acid,and the product was re-esterified to give diethyl2-aminonon-4-ynedioate, which was distilled to give a colourless oil,b.p. 116°/0.01 mm, n_(D) ¹⁷ 1.4703.

The foregoing amino-compound was reacted with oct-1-en-3-one to givediethyl 2-((3-oxooctyl)amino)-non-4-ynedioate which was reduced withsodium borohydride to give diethyl2-((3-hydroxyoctyl)amino)-4-ynedioate.

Treatment of this compound with potassium cyanate and hydrochloric acid,and hydrolysis of the hydantoin ester so produced gave a light brownoil. Purification by chromatography o a column of silica with a mixtureof chloroform and methanol (30:1) as eluante gave5-(6-carboxyhex-2-ynyl)-1-(3-hydroxyoctyl)hydantoin as a colourless oil,(mixture of diastereomers) showing two spots, Rf. 0.38, 0.44, when runin a chloroform, methanol, acetic acid (90:5:5) mixture on a thin layerof silica. By use of HPLC one of the diastercomeis (TLC, Rf. 0.38) wasisolated as a colourless oil; NMR (CDCl₃)δ0.89 (3H, triplet, --CH₃),2.2-2.4 (6H, multiplet, --CH₂, C═C.CH₂ --+--CH₂.CO₂ H), 3.54 (2H,triplet, >N.CH₂ --), ca 3,6 (1H, multiplet, >CH.OH), 4.11 (1H, triplet,>N.CH.CO--).

This compound was then catalytically hydrogenated to the corresponding5-(6-carboxyhex-2-enyl)-1-(3-hydroxyoctyl) hydantoin and subsequently tothe corresponding saturated compound which was found to be identicalwith the title compound of Example 2.

EXAMPLE 43 A. 2-(Dibutoxymethyl)glycine ethylester

N-Formylglycine ethyl ester was C-formylated using a method based onthat described by Harman and Hutchinson in J. Org. Chem. 1975 40, 3474and the resulting compound converted to 2-(dibutoxymethyl)glycine ethylester using the method described in "Chemistry of Penicillin", Eds. H.T. Clarke et al., published by Princetown University Press, New Jersey,1949 p. 517.

B. 1-(6-Carboxyhexyl)hydantoin-5-carboxaldehyde

A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g.) with ethyl7-bromoheptanoate (1.82 g.) was heated under nitrogen in a bath at 100°C. for 3 hr. to give crude ethyl7-((2,2-dibutoxy-1-ethoxycarbonylethyl)amino)-heptanoate hydrobromide. Astirred solution of 3.28 g. of this hydrobromide in ethanol (13 ml) wascooled in ice-water and treated with a solution of potassium cyanate(1.34 g) in water (4 ml), followed by 2N aqueous hydrochloric acid (3.63ml); the cooling bath was removed and stirring was continued at roomtemperature for 22 hr. The ethanol was evaporated in vacuo, the residuewas shaken with water and ether, and the ethereal solution wasseparated, washed with water and dried over magnesium sulphate (MgSO₄);removal of the ether left an oil which was heated under nitrogen at 100°C. for 3 hr., to give5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g.). This wasstirred in ether (6 ml) with water (48 ml) and N aqueous sodiumhydroxide (24.9 ml) at room temperature for 11/2 hr. and, after theaddition of more ether (50 ml), the aqueous phase was separated, cooled(ice-H₂ O), stirred with fresh ether and acidified to Congo Red with Naqueous hydrochloric acid. The ethereal solution of carboxylic acid wasthrice washed with water, dried (MgSO₄), and evaporated, to leave1-(6-carboxyhexyl)-5-dibutoxymethylhydantoin (2.15 g.) as a gum. When1.89 g. of the latter were cooled in ice-water and stirred withconcentrated aqueous hydrochloric acid (8.5 ml), the resulting solutiongave place spontaneously to a suspension of colourless crystals. Thesuspension was set aside at room temperature for 11/2 hr., diluted withwater (10 ml.) and set aside 15 min.; the crystals were then collected,washed with water, dried in vacuo, suspended in ether (3 ml), andcollected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde(0.74 g.), m.p. 223.5°-225° C. (Found: C. 51.86- H, 6.66; N, 10.62. C₁₁H₁₆ N₂ O₅ required C, 51.56; H, 6.29; N, 10.93%). In dimethylsulphoxide-d₆, this compound exists predominantly as the maskedaldehyde, 1-(6-carboxyhexyl)-5-hydroxymethylenehydantoin.

C. 1-(6-Carboxyhexyl)-5-((E)-3-oxo-octylidene)hydantoin

A mixture of 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (20 mg.) with2-oxoheptylidene-triphenylphosphorane (59 mg.) (see J. Org. Chem. (1972)37, 1818) and 1 drop of benzene was heated under nitrogen at 100° C. for35 min., and the resulting gum was taken up in ethyl acetate. Theproduct was extracted into dilute aqueous sodium bicarbonate, theextract was washed with ethyl acetate and acidified to Congo Red with Naqueous hydrochloric acid, and the liberated carboxylic acid wasextracted into ether. The ethereal solution was washed with water, dried(MgSO₄), and evaporated, to give a gum (25 mg.) which was identified by'H n.m.r. spectroscopy (characteristic signals at δ5.72 (1H, triplet,═GH--) and 3.93 (2H, doublet, ═CH--CH₂ --CO) with J 7.1 Hz, indeuterochloroform) as1-(6-carboxyhexyl)-5-((E)-3-oxo-octylidene)hydantoin.

D. 1-(6-Carboxyhexyl)-5-((E)-3-hydroxyoctylidene)hydantoin

A stirred solution of1-(6-carboxyhexyl)-5-((E)-3-oxooctylidene)hydantoin (20 mg.) in H₂ O(1.5 ml.) containing a slight excess of sodium bicarbonate was treatedwith sodium borohydride (5 mg.). After 60 min., the solution wasacidified to Congo Red with N aqueous hydrochloric acid, the liberatedcarboxylic acid was extracted into ethyl acetate, and the ethyl acetatesolution was thrice washed with water and dried (MgSO₄). Evaporation ofthe ethyl acetate left a pale yellow gum (14 mg.) which was identifiedby 'H n.m.r. spectroscopy (characteristic signal at δ5.61 (1H, triplet═CH--, J 7.1 Hz) in deuterochloroform as1-(6-carboxyhexyl)-5-((E)-3-hydroxyoctylidene)hydantoin.

E. 1-(6-Carboxyhexyl)-5-(3-hydroxyoctyl)hydantoin

The product described in paragraph C was substantially reduced to1-(6-carboxyhexyl)-5-(3-oxooctyl)hydantoin and the title compound whichwere found to be identical with the title compounds of Examples 28 and 2respectively.

In the following examples the hydantoins are designated thus:

Compound 2: 5-(6-Carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin

Compound 4: 5-(6-Carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin

Compound 6: 5-(6-Carboxyhexyl)-1-(3-hydroxynonyl)hydantoin

Compound 9: 5-(6-Carboxyhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin

Compound 11:5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclobutylpropyl)hydantoin

Compound 12:5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclopentylpropyl)hydantoin

Compound 14:5-(6-Carboxyhexyl)-1-(3-hydroxy-3-cyclohexylpropyl)hydantoin

Compound 38: 5-(6-Carboxyhexyl)-3-methyl-1-(3-oxooctyl)hydantoin.

Where a particular diastereomer is used, this is indicated by referenceto its melting point.

EXAMPLE A Cardiovascular effects in rats

Male normotensive rats Wistar (Charles River) strain, (250-350 g) wereanesthetised (chloroform) prior to cannulation of the left femoral veinand anaesthesia maintained by intravenous chloralose (60 mg/kg).Pulsatile blood pressure was recorded from the left femoral artery withan electronic transducer (Bell and Howell Type 4-327 L221) andintegrated heart rate was measured with a cardiotachometer triggeredfrom the arterial pressure waves. The test compound was administered asa solution in physiological saline by intravenous injection via thefemoral cannula. The responses recorded were allowed to return to thepreinjection levels between successive administrations.

Injections of the vehical alone in volumes equivalent to thosecontaining drug did not produce hypotension.

    ______________________________________                                                                 Mean fall in blood                                   Compound     Dose        pressure mmHg                                        ______________________________________                                        PGE.sub.2    4μg/kg   28                                                   PGE.sub.2    16μg/kg  44                                                   Compound 2   10μg/kg  14                                                   Compound 2   1mg/kg      42                                                   Compound 6   3mg/kg      40                                                   Compound 9   3mg/kg      22                                                   ______________________________________                                    

EXAMPLE B Inhibition of Platelet Aggregation

Aggregation of platelets in 1 ml. of fresh human platelet rich plasma(PRP) was monitored in a Born aggregometer.

The compound to be tested was added to the PRP at the desiredconcentration, and the resulting mixture incubated at 37° C. for 1minute after which platelet aggregation was stimulated by the additionof adenosine diphosphate (ADP) to a concentration of 5 μM.

The anti-aggregatory effect of the compound was assessed by measuringthe percentage inhibition of platelet aggregation in the presence of thecompound as compared when it was completely absent.

    ______________________________________                                        Compound   Concentration                                                                             % Inhibition of Aggregation                            ______________________________________                                        PGE.sub.1  15ng/ml     33                                                     PGE.sub.1  20ng/ml     47                                                     PGE.sub.1  30ng/ml     63                                                     PGE.sub.1  40ng/ml     69                                                     Compound 12                                                                              0.5ng/ml    25                                                     (m.p. 116°-117°)                                                Compound 12                                                                              1.0ng/ml    51                                                     (m.p. 116°-117°)                                                Compound 12                                                                              2.0ng/ml    79                                                     (m.p. 116°-117°)                                                Compound 12                                                                              4.0ng/ml    94                                                     (m.p. 116°-117°)                                                ______________________________________                                    

Using comparisons such as this the following relative potencies weredemonstrated with respect to PGE₁. Compound 2 (m.p. 76°-78°), 12.5x;Compound 4 (m.p. 144°-146°), 0.05x; Compound 11 (114°-116°), 5.2x;Compound 12 (m.p. 116°-117°), 12.5x; and Compound 14 (m.p. 96°-98°),16x.

EXAMPLE C

Compound 38 was found to reduce aspirin-indused gastric ulceration inrats: an oral dose of 1 mg/kg gave 80% protection.

EXAMPLE D

At an intravenous dose of 30 μg/kg, Compound 2 completely inhibitedpentagastrin-induced gastric acid secretion in rats.

EXAMPLE E

An intravenous injection of Compound 9 (50 μg/kg) was found tocompletely anatagonise histamine-reduced broncho-constriction inanaesthetised guinea-pigs.

EXAMPLE F

Intravenous infusions of Compound 2 (m.p. 76°-78° C.) at a dose of 250μg/min have been found to reduce electrically-induced arterialthrombosis in anaesthetised rabbits.

EXAMPLE G

    ______________________________________                                        Tablet                 In one tablet                                          ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                           5.0 mg                                                 Lactose B.P.           82.0 mg                                                Starch B.P.            10.0 mg                                                Povidone B.P.C.        2.0 mg                                                 Magnesium Stearate     1.0 mg                                                 ______________________________________                                    

Mix together the Compound 12, lactose and starch. Granulate the powdersusing a solution of the povidone in Purified Water. Dry the granules,add the Magnesium Stearate and compress to produce tablets, 100 mg pertablet.

EXAMPLE H

    ______________________________________                                        Capsule                In one capsule                                         ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                           10 mg                                                  Lactose                79 mg                                                  Starch                 10 mg                                                  Magnesium Stearate      1 mg                                                  ______________________________________                                    

Mix the powders in a powder blender, fill into hard gelatin capsules,100 mg per capsule.

EXAMPLE I

    ______________________________________                                        1 μg/ml Injection                                                          ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                             100 μg                                            Water for Injection to   100 ml                                               ______________________________________                                    

Dissolve the Compound 12 in the Water for Injection. Sterilise thesolution by filtration through a membrane filter, 0.22 μm pore size,collecting the filtrate in a sterile receiver. Under aseptic conditions,fill the solution into sterile glass ampoules, 1 ml per ampoule. Seal byfusion of the glass.

EXAMPLE J

    ______________________________________                                        10 μg/ml Injection                                                         ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                              1 mg                                                Ethyl Alcohol             10 ml                                               Propylene Glycol          30 ml                                               Water for Injection to   100 ml                                               ______________________________________                                    

Dissolve the Compound 12 in the Ethyl Alcohol, add the Propylene glycoland dilute to volume with Water for Injection.

Sterilise the solution by filtration through a membrane filter, 0.22 μmpore size, collecting the filtrate in a sterile vessel. Under asepticconditions, fill the solution into sterile glass vials, 10 ml per vial.Close with a sterile rubber plug and secure with an aluminium collar.

EXAMPLE K

    ______________________________________                                        100 μg Single dose injection (freeze-dried)                                ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                             10.0 mg                                              Mannitol                 2.5 g                                                N/10 Sodium Hydroxide Solution                                                                         qs to pH 10.0                                        Water for Injection to   100.0 ml                                             ______________________________________                                    

Suspend the Compound 12 in approximately 20 ml Water. Add sufficientSodium Hydroxide Solution to produce pH 10 and stir to dissolve theCompound 12. Add and dissolve the Mannitol and dilute to volume withWater for Injection.

Sterilise the solution by passage through a membrane filter, 0.22 μmpore size and distribute aseptically into sterile vials, 1 ml per vial.Freeze dry the solutions and seal the containers under asepticconditions with rubber closures. Each vail contains 100 μg Compound 12as its freeze-dried Sodium salt.

EXAMPLE L

    ______________________________________                                        Suppository                                                                   ______________________________________                                        Compound 12 (m.p. 116°-117°)                                                              3 mg                                                Massa Esterinum C to      2 mg                                                ______________________________________                                    

Melt the suppository base at around 40° C. Gradually incorporate theCompound 12 in fine powder and mix until homogeneous Pour into suitablemoulds and allow to set.

Massa Esterinum C is a commerically available suppository baseconsisting of a mixture of mono-, di- and tri-glycerides of saturatedvegetable fatty acids. It is marketed by Henkel International,Dusseldorf.

What we claim is:
 1. A compound of formula ##STR16## wherein Z ishydrogen or alkyl;M is >C═Z³, >CH--CHO or >CH--CH(OG³)₂, G³ being alkyl;and Z⁴ is --CH₂ --X--X¹ --X² or --Y--Y¹ --Y² --Y³, except when M is C═Z³whereuponeither Z³ is ═CR--CH₂ --Y¹ --Y² --Y³ and Z⁴ is --CH₂ --X--X¹--X², or Z³ is ═CH--X--X¹ --X² and Z⁴ is --Y--Y¹ --Y² --Y³ ;wherein R ishydrogen or methyl; X is phenylene, --C.tbd.C--, --CH═CH-- or --CH₂--CQ₂ --, in which each Q is independently selected from hydrogen andalkyl or the two Q's together form an alkylene radical having four, fiveor six carbon atoms; X¹ is a covalent bond or a straight or branchedalkylene chain having 1 to 6 carbon atoms, optionally having one of itsmethylene groups replaced by oxa (--O--) provided that at least onecarbon atom separates the oxa group from a --C.tbd.C--, --CH═CH-- or--CO-- group; X² is selected from 5-tetrazolyl, carboxyl, carboxamide,hydroxymethylene and alkoxycarbonyl; Y is --CR₂ --CH₂ --in which each Ris independently as defined above; Y¹ is carbonyl, methylene, methylenesubstituted by hydroxyl, or methylene substituted by hydroxyl and alkyl;Y² is a covalent bond or straight or branched alkylene having 1 to 7carbon atoms, optionally substituted on the carbon adjacent Y¹ by one ortwo groups independently selected from alkyl, cycloalkyl andbicycloalkyl; and Y³ is hydrogen, hydroxy, alkoxy having 1 to 7 carbonatoms, cycloalkyl, bicycloalkyl, phenyl, benzyl, phenoxy orbenzyloxy,wherein each of phenyl, benzyl, phenoxy and benzyloxy may besubstituted in the benzene ring by one or more groups selected fromhydroxy, halogeno, nitro, amino, acylamino, alkenyl, alkoxy, phenyl, andalkyl which may itself be substituted by one or more halogeno groups; orY is a bond, --CH₂ -- or --CH₂.CH₂ --; and Y¹, Y² and Y³ taken togetherform a cycloalkyl group substituted by a hydroxyl group;and saltsthereof.
 2. The compound is1-(6-carboxyhexyl)-5-((E)-3-hydroxyoctylidene)hydantoin.